Objective Primary stenting for acute ischemic stroke (AIS) using the Wingspan stent delivery system has been reported. Major technical limitations in that study were difficulties in delivering the device and a few cases in which the Enterprise vascular reconstruction device (stent) was used as a bailout procedure. The Enterprise, which has relatively less radial force and more flexibility than other intracranial stents, is an ideal device for revascularization as it is easily delivered through tortuous intracranial vessels. We tested the safety and effectiveness of this stent as the primary revascularization device for AIS in an FDA-approved investigational device exemption prospective cohort study.
Methods Twenty patients presenting with AIS due to confirmed intracranial large vessel occlusion within 8 h of onset of stroke symptoms were treated with the Enterprise as the primary revascularization device. The primary outcome was recanalization to Thrombolysis In Myocardial Infarction (TIMI) flow of ≥2. Perioperative safety was measured by major complication incidence within 30 days of stent revascularization. A secondary measure of outcome was 30-day modified Rankin Scale (mRS) score.
Results Recanalization to TIMI 2 (n=6) or 3 (n=12) flow was achieved in 18 patients (90% revascularization rate). Three major complications were noted (15%) including one myocardial infarction, one symptomatic intracranial hemorrhage and one ischemic stroke in a distribution other than the qualifying vessel. Good outcome (mRS ≤2) was obtained in 10 patients (50%).
Conclusions In this prospective study the Enterprise stent was found to be a safe and effective revascularization tool in the setting of AIS.
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The use of retrievable stent-like revascularization devices to perform thrombectomy for large-vessel occlusions in the setting of acute ischemic stroke (AIS) results in higher recanalization rates and reduced morbidity and mortality compared with first-generation thrombectomy devices.1 ,2 However, there remains a significant subset of patients in whom placement of the stent retriever results in immediate recanalization but retrieval results in reocclusion. This pattern results in repeat instances of crossing the target lesion and likely embolic events in distal or unaffected territories in up to 9% of cases.1 ,2 This behavior probably reflects the underlying clot/embolus characteristics or instances of underlying intracranial atherosclerotic disease with plaque rupture/thrombosis. The Enterprise stent (Codman, Raynham, Massachusetts, USA) is a self-expanding closed-cell stent that has been employed as a revascularization device for compassionate use in AIS after other devices have failed. By virtue of its closed-cell nature and delivery mechanism, the Enterprise stent is retrievable for up to 70% of its deployed length. However, it can be easily deployed as well. These unique properties make this device an optimal solution for AIS revascularization via stent retrieval, stent implantation, or both. This device received Food and Drug Administration (FDA) approval in 2007 under the humanitarian device exemption program for use in conjunction with detachable coils for the treatment of wide-necked cerebral aneurysms. The Enterprise-assisted Recanalization in Acute Ischemic Stroke (ERAIS) prospective phase I study, an FDA-approved investigational device exemption (IDE) study, was designed to test the safety of the Enterprise stent as the primary revascularization device in cerebral revascularization. The principal benefits of this self-expanding closed-cell stent include ease of delivery and less radial force compared with other self-expanding stents designed for intracranial use.
Design, setting, participants and study size
After consultation with the local Institutional Review Board and the FDA, approval for this prospective single-center cohort study was obtained with a planned enrollment of 20 patients. This sample size was thought to be sufficient to display safety for this device compared with similar devices employed for AIS revascularization. Enrollment was completed in two phases between 1 July 2010 and 1 April 2011 and between 12 October 2011 and 22 June 2012. There was a gap in the enrollment because, during this period, eligible patients were preferentially enrolled into the multicenter SOLITAIRE FR With the Intention For Thrombectomy (SWIFT) and Thrombectomy REvascularization of large Vessel Occlusions (TREVO) 2 trials.1 ,2 Patients presenting with AIS within 8 h of stroke symptom onset with contraindication to intravenous thrombolysis or with no clinical improvement 1 h after administration of intravenous thrombolysis were eligible for entry in the ERAIS study if they met the predetermined inclusion and exclusion criteria (box 1).
Study inclusion and exclusion criteria
Severe clinical symptoms of ischemic stroke with National Institutes of Health Stroke Scale score ≥8
Age ≥18 years
Angiographic demonstration of focal occlusion in the middle cerebral artery (MCA), intracranial internal carotid artery, intracranial vertebral artery, posterior cerebral artery or basilar artery measuring ≤30 mm in length
Target lesion located in an intracranial artery that is ≤4.5 mm in diameter
Stroke symptoms and CT stroke study evidence of a perfusion deficit with a significant viable penumbra attributed to the target lesion
Inability to obtain informed consent; patient is a ward of the state; patient entry into the study is within 30 days of participation in a separate investigational drug or device study
Baseline glucose level <50 mg/dL
Known hemorrhagic diathesis, coagulation factor deficiency or oral anticoagulant therapy with international normalized ratio >3.0; baseline platelet count <100 000
Pre-existing neurologic or psychiatric disease that could impede the study results
History of severe allergy to intra-arterial contrast medium, aspirin, clopidogrel, ticlopidine, eptifibatide or nickel titanium that prohibits their use
Severe sustained hypertension (systolic blood pressure >180 mm Hg, diastolic blood pressure >110 mm Hg) unable to be controlled by antihypertensive therapy prior to planned intervention
Signs of completed infarction on non-contrast CT scan of the brain (mass effect or hypodensity of more than one-third of the vascular distribution of the affected MCA)
Anticipated life expectancy <12 months
Extensive clot burden (>30 mm in length) or multiple areas of occlusion; known ischemic stroke within the past 30 days; known hemorrhagic stroke within the last 60 days
Dependence on renal dialysis or known serum creatinine level >2.0
CT perfusion imaging demonstrates more than one-third of the ‘at-risk’ tissue is non-salvageable (cerebral blood flow or cerebral blood volume <50% of the contralateral non-diseased brain)
Any active or suspected systemic infection
Patients were recruited after they underwent a CT stroke study that included non-contrast CT scanning of the brain, CT angiography from the aortic arch to the vertex of the head and CT perfusion imaging using a 360-slice CT scanner (Toshiba Medical Systems, Tustin, California, USA). The images were reconstructed on a Vitrea workstation (Toshiba Medical Systems) to confirm that patients met the inclusion and exclusion criteria.
After consenting to participate in the study, patients received a loading dose (orally or through a nasogastric tube) of aspirin (650 mg) and clopidogrel (600 mg). They were brought to a biplane angiography suite where the stroke intervention was performed. When possible, anesthesia was limited to conscious sedation which allowed for frequent neurological examination throughout the procedure. Patients unable to tolerate conscious sedation (eg, those who were restless or anxious) were intubated and sedated with propofol. Standard femoral artery access was obtained and a guide catheter was placed using fluoroscopic visualization with roadmap guidance into a non-occlusive position proximal to the affected vessel. Typically, a 6- or 7-Fr guide catheter with an occlusive balloon (Concentric Medical, Mountain View, California, USA) was employed for the procedure. Heparin was administered with a goal activated coagulation time between 250 and 300 s. A microcatheter was directed over a steerable microwire into position just past the area of occlusion under roadmap visualization and a combined microrun/guide catheter run was performed to document the occlusion. Procedure start time was considered the time of groin puncture.
The Enterprise stent is available in a single diameter (4.5 mm) and multiple lengths (14, 22, 28 and 37 mm), chosen at the discretion of the operator. The study protocol did not delineate the specific revascularization technique. The device was deployed or used as a thrombectomy device based on operator preference. The typical rationale for deployment was in earlier cases (from symptom onset) with perfusion imaging suggesting little to no infarct core and therefore lower risk of hemorrhagic transformation with or without dual antiplatelet therapy. However, in later cases or those with established areas of infarcted core (although less than 30%), it was felt to be better to retrieve the stent and avoid the need for dual antiplatelet therapy post-procedure. Finally, if stent retrieval resulted in reocclusion, the stent was deployed during a subsequent delivery. For deployment cases the stent was deployed across the occlusion with or without pre- or post-balloon angioplasty at the site of vessel occlusion based on operator preference. For thrombectomy cases, the Enterprise stent was partially delivered (50–70% of the total length) into position at the site of the vessel occlusion. Typical practice at our center is to test patency of the occluded vessel with angiography from the guide catheter after each partial delivery, and a period of 3–5 min of ‘temporary bypass’ is allotted to perfuse the brain and encourage the thrombus to become integrated within the stent. At this point the balloon at the distal guide tip is inflated and the partially deployed stent and microcatheter are then removed as a unit under aspiration through the guide catheter (approximately 20–60 mL) to remove any thrombus debris from the occluded parent vessel and guide catheter. Thereafter, the guide catheter balloon is deflated to restore flow. Angiography is then performed to assess the revascularization effort. Up to three deployment/thrombectomy attempts were permitted within the parameters of the ERAIS study.
Variables, data sources/measurement and bias
The primary study outcome was revascularization to thrombolysis in myocardial infarction (TIMI) flow of 2 or 3 (delayed distal flow or distal flow without significant delay). This score was recorded at the time of the procedure and determined by the senior surgeon. Perioperative safety was measured by the presence or absence of symptomatic intracranial hemorrhage (SICH) and major complication rate within 30 days of stent revascularization. SICH was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥4 points in conjunction with a hemorrhage on follow-up imaging that was not seen on a previous study. Clinical outcome parameters included change in NIHSS score for surviving patients at discharge and 30-day modified Rankin scale (mRS) score. Major complications included SICH, access site hematoma resulting in a fall of ≥10 points in the hematocrit level or necessitating blood transfusion, intraoperative vessel perforation resulting in extravasation, bleeding in other organ systems necessitating medical intervention or prolonging hospitalization, access site infection, ischemic stroke in a distribution other than the qualifying vessel, myocardial infarction (MI) and any death attributable to the intervention or in patients demonstrating worsened NIHSS scores (≥4 points) in whom care was withdrawn in accordance with the wishes of the family. Relevant demographic data were obtained for each patient. Secondary outcome measures including mortality (not attributed to any major complication), minor complications and time to revascularization (from groin puncture to time of final revascularization) were noted.
Outcome variables were reported by the treating team. These included TIMI score and time to revascularization, major complications, 30-day follow-up measures and relevant demographic data. Self-reporting of variables represents a potential source of bias but was necessary due to limitations in funding. Funding by the Codman Corporation for this study (supply of study devices) also represents a potential conflict of interest for two of the authors.
Follow-up through 30 days was available for all 20 patients. Relevant demographic data were reported as mean±SD or percentage where appropriate. Outcome variables including revascularization, good outcome (mRS score ≤2) and major complications were reported as a percentage. Time to revascularization was reported as both mean±SD and median±SD. Simple statistical measurements were calculated using Microsoft Excel V.2010 (Microsoft Corporation, Redmond, Washington, USA).
Twenty-four patients were screened and were eligible for recruitment in the study. Four of these patients did not participate for the following reasons: patient refusal (n=1), excessive clot burden of >30 mm in length (n=1), entry into another study (n=1) and recanalization of occluded vessel with intravenous tissue plasminogen activator (tPA, n=1). Twenty patients (13 women) of average age of 70.1±13.0 years were therefore enrolled in the study. The demographic and clinical characteristics of these patients are summarized in table 1. The number of patients enrolled with known comorbidities was as follows: 7 with diabetes mellitus, 15 with hypertension, 9 with hypercholesterolemia, 7 with atrial fibrillation and 10 patients were current or former smokers. All patients had intracranial large vessel occlusion (TIMI 0) with an average preoperative NIHSS score of 15.5±1.3. Vessel occlusion sites were the middle cerebral artery (MCA) only in 15 patients, intracranial internal carotid artery (ICA) only in 2, basilar artery in 2 and combined carotid terminus/MCA in 1. Six patients had intravenous tPA without clinical improvement before enrollment. Pre-treatment (n=1) or post-treatment (n=9) balloon dilation was used in 10 patients. The stent was implanted in 13 patients and used as a thrombectomy device and thus retrieved in 7 patients. Twenty-four stents were used in 20 patients. Three patients had multiple stents used, with two stents implanted among these patients and the remaining stents retrieved. Although the Enterprise stent was engineered to be resheathed after <80% of the stent was unsheathed, we encountered resheathing problems on the table after a first thrombectomy attempt and prior to a second thrombectomy attempt in two of the above cases, after which multiple stents needed to be used for complete recovery of the thrombus. One stent was inadvertently deployed (case described in figure 1).
The time from the start of the procedure to TIMI 2 or 3 recanalization was 43±21 min (mean±SD) or 40±21 min (median±SD), with a range from 16 min to 102 min. The longest was the patient with combined carotid terminus and MCA occlusion (case 5) requiring navigation from the contralateral ICA via the anterior communicating artery complex. Excluding this case, mean±SD time from start of procedure to recanalization was 40±15 min.
Recanalization to TIMI 2 (n=6) or 3 (n=12) flow was achieved in 18 of the 20 patients (90% revascularization rate). Of note, both patients in whom we were not able to achieve TIMI 2 or 3 recanalization (cases 11 and 12) survived and had improvement of NIHSS scores from baseline values (from 12 to 2 and from 21 to 13, respectively). The first recovered to an mRS score of 0 and the second remained with an mRS score of 4 at the 30-day follow-up evaluation. Both patients had received intravenous tPA prior to the attempted revascularization procedure.
Three major complications (15%) were noted, including one MI, one SICH and one ischemic stroke in a distribution other than the qualifying vessel. Eight minor complications were noted. Seven (35%) patients died within 30 days of revascularization (four in hospital). Stroke or stroke-related complications were the direct cause of death in six of the seven patients who died. Three patients died in part as a consequence of major complications, including the patient with ischemic stroke in a distribution other than the target vessel (case 4), another due to ventricular fibrillation after an MI (case 9) and another with SICH with worsening of the NIHSS score from 12 at presentation to 25 at 24 h (case 14). Among the 13 survivors, the NIHSS score improved from admission to time of discharge by an average of 11.5±1.8 points. Among the survivors, 10 patients (50%) improved to an mRS score of 0–2 within 30 days after the intervention (mRS scores: 0, n=6; 1, n=2; 2, n=2).
This study represents the first reported FDA-approved IDE use of the Enterprise device for revascularization in the setting of AIS. This phase I study displayed safety and efficacy of the Enterprise stent comparable with that of the Wingspan device,3 the Solitaire device,4 the Penumbra system5 or the Trevo device6 in their respective phase I trials (table 2). Unlike the Trevo but similar to the Solitaire, this closed-cell stent offers the flexibility of temporary or permanent endovascular bypass in the setting of AIS. In the setting of intracranial atherosclerosis or recurrent occlusion after device retrieval, it may offer superior results where thrombectomy is often ineffective and the potential risk of iatrogenic vessel injury is greater. Furthermore, the Enterprise stent is more easily delivered than the Wingspan stent and more easily deployed than the Solitaire stent.
The Enterprise stent has been used successfully for salvage therapy in the setting of stroke intervention after failed attempts at revascularization with Merci (Concentric Medical) retrieval or Penumbra (Penumbra, Alameda, California, USA) aspiration.7–9 In a previous multicenter retrospective review of data prospectively collected for 20 patients with AIS (mean presentation NIHSS score of 17) treated with Enterprise stent placement as a bail-out procedure after other embolectomy options had been exploited, TIMI 2 or 3 recanalization was achieved in all patients with improvement in the NIHSS score of >4 points at discharge in 75% of patients.10 Included in this report were three cases of failed Wingspan stenting that were subsequently treated with successful deployment of the more navigable Enterprise stent at the occlusion site. Closed-cell stents like the Enterprise can be used for temporary endovascular bypass with resheathing and removal of the stent after recanalization is achieved, obviating the need for protracted post-procedure dual antiplatelet therapy. In addition, this technique should eliminate the potential risk of delayed in-stent stenosis associated with permanent stent deployment. It should be noted that, although in-stent stenosis is significant (8–35%) when using stents for intracranial atherosclerotic disease,11–15 it is relatively infrequent (3%) and less likely to be symptomatic when using stents for intracranial aneurysms16–18 where, as in most cases of AIS, there are no significant anomalies in the underlying vasculature.
Kelly et al19 and Hauck et al20 each reported a case where the Enterprise was used as a temporary endovascular bypass in the acute stroke setting. In both cases the stent was partially deployed and then retrieved, with successful recanalization of the occluded vessel. Gonzalez et al21 reported use of the Enterprise as a temporary bypass in seven cases. These initial reports led contemporaneously to the development of the Solitaire (designed similarly for coil-assisted aneurysm embolization) for use as a stent retriever in AIS22 and subsequently to the development of the entire generation of stent retriever devices.
The landmark SWIFT2 and TREVO 21 trials have clearly established the superiority of stent retrievers over the first-generation Merci mechanical retriever. However, there remains the issue of need for multiple passes with the device because of recurrent occlusion after retrieval of a deployed stent retriever. These events are most likely to occur when there is an underlying intracranial atherosclerotic thrombotic plaque or when the consistency of the embolus is such that it is too adherent to the vessel wall and allows the stent to be retrieved through it without gathering the clot. In these cases additional passes are required and, with each pass, there are concerns for vessel injury, distal embolization from clot fragmentation or embolization into unaffected territories and delay in recanalization of ischemic brain. In these situations it may be useful to deploy the stent either on the initial attempt or after one failed pass. Similarly, if initial perfusion imaging suggests no core infarct and the patient presents early after stroke symptom onset, primary stenting may be safer and faster because of lower concerns for intracerebral hemorrhage in light of the need for protracted dual antiplatelet therapy. Conversely, established core infarcts (with significant salvageable penumbra (≥70%)) or delayed presentations may be better cases for stent retrieval because of heightened concern for intracerebral hemorrhage, which may potentially be aggravated by dual antiplatelet therapy. The one concern we had in this study was the 50% incidence of need for adjunctive angioplasty, typically after stent deployment. This reflects the very low outward radial force of the Enterprise stent. This was much less frequently encountered during the previous study with Wingspan stenting for AIS.3 The ideal stent/stent retriever should have a higher force than the Enterprise to obviate the need for post-procedure angioplasty, a closed-cell design to trap more thrombus outside the tines of the stent and allow recapture of the device for retrieval, and ability to fully deploy the stent while maintaining ability to retrieve or deploy it.
Employing two separate reperfusion strategies with the same device represents a limitation of this study. In a review of the cases, it may be noted that revascularization was successful in all 13 cases with stent implantation but in only five of seven cases with no stent implantation. This may suggest that stent implantation represents the best revascularization strategy with the Enterprise device. Such benefits must be weighed against the risk of hemorrhage assumed with dual antiplatelet therapy in the setting of AIS. It is notable that the single symptomatic intracranial hematoma in this study occurred in a patient undergoing stent implantation (and continued dual antiplatelet therapy). In patients in whom no stent implantation was performed and revascularization was unsuccessful, the risks of dual antiplatelet therapy were thought to outweigh the benefits of stent implantation.
As no cerebral revascularization device is failsafe, it is most beneficial to the surgeon and patient to have multiple cerebral revascularization devices available for use. Physician-directed FDA-approved device trials such as ERAIS will help continue the advancement of endovascular treatment of AIS. Larger studies with blinded adjudicated endpoints including imaging are needed to definitively evaluate dual-purpose primary stenting/stent retrieval-capable devices for establishing efficacy, particularly against retrieval-only platforms.
In this prospective pilot study the Enterprise stent was shown to be a safe primary revascularization device in the setting of AIS. Further study is required to determine its efficacy compared with other revascularization devices.
We thank Paul H Dressel BFA for assistance with illustration preparation and Debra J Zimmer for editorial assistance.
Contributors EIL, JM: conception and design. TMD, SKN: literature research, statistical analysis and drafting the manuscript. AHS: drafting the manuscript. All authors were involved in acquisition of data, analysis and interpretation of data, critically revision of the manuscript and approval of the final manuscript.
Funding Funding and study devices were provided by Codman; however, data collection, analysis, and interpretation were performed by the authors, independent of the company's input or interpretation.
Competing interests LNH: grant, Toshiba; consultant: Abbott, Boston Scientific, Cordis, Micrus, Silk Road; financial interests: AccessClosure, Augmenix, Boston Scientific, Claret Medical, Endomation, Micrus, Valor Medical; board/trustee/officer position: Access Closure, Claret Medical; speakers’ bureau: Abbott Vascular; honoraria: Bard, Boston Scientific, Cleveland Clinic, Complete Conference Management, Cordis, Memorial Health Care System, Society for Cardiovascular Angiography and Interventions (SCAI). EIL: grant (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices) and honoraria: Boston Scientific; research support: Codman, ev3/Covidien Vascular Therapies; ownership interests: Intratech Medical, Mynx/Access Closure; consultant: Codman, ev3/Covidien Vascular Therapies, TheraSyn Sensors; fees for carotid stent training: Abbott Vascular, ev3/Covidien Vascular Therapies. EJM: consultant: NFocus, Lazarus Effect, Endeaver Endovascular. AHS: grants from National Institutes of Health (co-investigator: NINDS 1R01NS064592-01A1, not related to present submission), University at Buffalo; financial interests: Hotspur, Intratech Medical, StimSox, Valor Medical, Blockade Medical; consultant: Codman & Shurtleff, Concentric Medical, Covidien Vascular Therapies, GuidePoint Global Consulting, Penumbra, Stryker Neurovascular, Pulsar Vascular; speakers’ bureaus: Codman & Shurtleff, Genentech; serves on National Steering Committees for Penumbra 3D Separator Trial, Covidien SWIFT PRIME Trial; advisory board: Codman & Shurtleff, Covidien Vascular Therapies; honoraria: American Association of Neurological Surgeons’ courses, Annual Peripheral Angioplasty and All That Jazz Course, Penumbra, Abbott Vascular and Codman & Shurtleff for training other neurointerventionists in carotid stenting and for training physicians in endovascular stenting for aneurysms. KVS: consultant, speakers’ bureau, honoraria: Toshiba; speakers’ bureau and honoraria: ev3, The Stroke Group. TMD, SKN, JLE, WHK: none.
Ethics approval The institutional review board at the University at Buffalo, State University of New York, approved this study (project NSG1700110A) and a standard Health Insurance Portability and Accountability Act-compliant protocol was followed.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Unpublished anonymised/de-identified data may be available. This would be on a per-request basis.